Cigarette smoking is a major public health problem in the United States, and nicotine is the principal pharmacological component of tobacco which reinforces smoking behavior. There is compelling evidence that nicotine produces its reinforcing effects by acting on nicotinic cholinergic receptors located on mesolimbic neurons in the brain which release dopamine from terminals of the nucleus accumbens. Studies of nicotinic receptors in other brain areas or in peripheral nerves have shown that, while brief exposure to nicotine produces receptor activation, prolonged exposure to even very low concentrations of nicotine (below the threshold for stimulation) results in receptor desensitization, whereupon subsequent exposure to nicotine does not produce the characteristic functional response. When one considers the blood and brain concentration of nicotine which are present in cigarette smokers throughout the day, it would seem that their receptors should be in a continual state of desensitization. How, then, could nicotine produce any significant reinforcing activity if the receptors upon which it acts have been rendered non-functional? There are a number of possible explanations which will be investigated in the present project. (1) It is possible that the receptors on the mesolimbic neurons do not display the desensitization characteristics determined in previous studies in other tissues and preparations. (2) It is also likely that, even during prolonged desensitization, the nicotine receptors on mesolimbic neurons exhibit sufficient basal or persistent activity to remain functionally responsive to nicotine. (3) There is evidence that glutamate neurons at the somatodendrites or the terminals of mesolimbic neurons can contribute to and perhaps enhance nicotine-stimulated dopamine release. (4) It is possible that the increased number of nicotinic receptors which result from chronic drug administration produces an increased response or that these receptors display different desensitization characteristics. These possibilities will be investigated by measuring the functional activity of mesolimbic receptors in intact slices of the ventral tegmental area and nucleus accumbens from nicotine-treated and nontreated rats. The nicotine-stimulated efflux of rubidium following various nicotine treatment schedules, coupled with assays of nicotine brain levels and receptors, will provide valuable new information about how mesolimbic neurons respond to nicotine. These studies are important as we attempt to understand the mechanisms responsible for cigarette smoking and nicotine dependence, as new nicotine replacement therapies become available for smoking cessation, and as nicotine and nicotine analogs find a place in therapeutics for such diseases as Alzheimer's, Parkinson's, ulcerative cholitis, schizophrenia and others.